Fasting protects against proteostasis defects induced by hypoxia

Abstract

When blood flow to various parts of the body becomes restricted, those tissues suffer from a lack of oxygen, a condition called hypoxia. Hypoxia can impair essential physiological processes and cause cellular damage and death, such as is observed as a result of stroke and cardiovascular disease. We have found that specific concentrations of hypoxia cause a disruption of protein homeostasis in C. elegans. However, the genetic signaling pathways involved in hypoxia-induced proteostasis defects remain poorly defined. Furthermore, although animals must respond appropriately to hypoxia in order to survive, a lack of oxygen may not be the only environmental stress with which an animal needs to contend. Yet the ways in which organisms integrate responses to the presence of multiple environmental stresses is also not well understood. In my dissertation research, I utilized the nematode C. elegans to study the response to hypoxia in conjunction with nutrient deprivation. I show that nutritional cues regulate the effect of hypoxia on proteostasis and that both the insulin/IGF-1 signaling (IIS) pathway and AMP-activated protein kinase (AMPK) play roles in mediating the effects of hypoxia and nutrient deprivation on protein aggregation. Animals that are fasted prior to hypoxic exposure develop dramatically fewer protein aggregates compared to their fed counterparts. I discovered that IIS is required for fasting protection, as animals with mutations in daf-2, the C. elegans insulin/IGF-1-receptor, display wild-type levels of hypoxia-induced protein aggregation upon exposure to hypoxia when fed, but are not protected by fasting. However, this requirement for IIS is independent of the downstream transcription factor DAF-16/FOXO. Furthermore, I found a role for AMPK in regulating the response to hypoxia that depends on the nutritional status of the animal. In fed conditions AMPK promotes protein aggregation, but without food AMPK is required for fasting-induced protection against aggregation. Taken together, my results outline a non-canonical role for the IIS pathway in coordinating the effects of both hypoxia and nutritional state on proteostasis, and also underscore AMPK’s role in modulating cellular pathways that maintain proteostasis in response to a complex interaction of environmental cues.